The Na/K-ATPase, also known as the sodium pump, is a ubiquitous trans-membrane enzyme that transports Na+ and K+ across the plasma membrane by hydrolyzing ATP. It belongs to the family of P-type ATPase that transits between E1 and E2 conformational states during pumping cycles. The functional enzyme is mainly composed of α and β subunits. The α subunit is the catalytic component of the holoenzyme as it contains both the nucleotide and the cation binding sites. Interestingly, studies during the past few years have uncovered many non-pumping functions of Na/K-ATPase such as signal transduction. Specifically, the signaling Na/K-ATPase resides in caveolae and interacts with a number of signaling proteins such as Src, IP3 receptor and caveolin-1. While the interaction between Na/K-ATPase and IP3 receptor facilitates Ca2+ signaling, the dynamic association between Na/K-ATPase and Src regulates cellular Src activity and makes it possible for cardiotonic steroids to stimulate protein kinase cascades.
Cardiotonic steroids (CTS) include plant-derived digitalis drugs such as digoxin and ouabain, and vertebrate-derived aglycones such as bufalin and marinobufagenin (MBG).
Although CTS have been considered only as drugs since their discovery, recent studies have identified both ouabain and MBG as endogenous steroids whose production and secretion are regulated by multiple stimuli including angiotensin II and adrenocorticotropic hormone (ACTH). Of the circulating CTS that have been identified and characterized, ouabain remains the most studied. Moreover, the concentrations of CTS were markedly increased under clinical conditions of high salt loading, chronic renal failure (CRF), and congestive heart failure (CHF). Clinically, digitalis drugs can be used to treat congestive heart failure because they have the well-documented inotropic effects on the heart.
Clinically, these steroids can be used to treat congestive heart failure because they have the well-documented inotropic effects on the heart. It is known that the Na/K-ATPase serves as a receptor for these steroids. While binding of CTS to the Na/K-ATPase inhibits the pumping function, it stimulates the signaling function of Na/K-ATPase. For example, binding of ouabain to the Na/K-ATPase/Src receptor complex stimulates Src kinase. The activated Src, in turn, trans-activates receptor tyrosine kinases such as EGF receptor (EGFR) and converts the tyrosine kinase signal to the stimulation of serine/threonine kinases, lipid kinases and lipases as well as increased production of reactive oxygen species (ROS). Interestingly, while inhibition of Na/K-ATPase by CTS is essential for these drugs to increase cardiac contractile function, stimulation of protein kinases and subsequent increases in the production of ROS by these steroids also cause cardiac hypertrophy and fibrosis in animal studies.
Several of the co-inventors herein have discovered “Na+/K+-ATPase Ligand,” as disclosed in the pending application U.S. Ser. No. 12/087,976 filed Jul. 31, 2008 (claiming priority from PCT/US07/002,365, filed Jan. 30, 2007 (Pub. No. WO 2007/089688 on Aug. 9, 2007), claiming priority from U.S. Ser. No. 60/763,783 filed Jan. 31, 2006), which applications are expressly incorporated herein by reference.
Several of the co-inventors herein have discovered “Na+/K+-ATPase-Specific Peptide Inhibitors/Activators of Src and Src Family Kinases,” as disclosed in the pending application U.S. Ser. No. 12/446,856 filed Apr. 23, 2009 (claiming priority from PCT/US07/023,011, filed Oct. 17, 2007 (Pub. No. WO 2008/054792 on May 8, 2008), claiming priority from U.S. Ser. No. 60/855,482 filed Oct. 16, 2006) which are expressly incorporated herein by reference.
Also, several of the co-inventors herein have discovered “Methods Regulating Na+/K+-ATPase Expression and Uses thereof. As Therapy for Cancer,” as disclosed in the application U.S. Ser. No. 61/109,386 filed Oct. 28, 2008, which is expressly incorporated herein by reference.
Also, several of the co-inventors herein have discovered “Na+/K+-ATPase-derived Peptides as Antagonists of CTS and as Therapeutic Agents for Cancer,” as disclosed in the pending application U.S. Ser. No. 61/122,205, filed Dec. 12, 2008, which is expressly incorporated herein by reference.